12-7089732-G-T

Variant names:

• chr12-7089732-G-T
• rs147288661
• NM_001733.7:c.426C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001733.7(C1R):​c.426C>A​(p.Asp142Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: C1R NM_001733.7 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.26

Genes affected

C1R (HGNC:1246): (complement C1r) This gene encodes a member of the peptidase S1 protein family. The encoded protein is a proteolytic subunit in the complement system C1 complex. The complement system acts as a mediator in the innate immune response by ultimately triggering phagocytosis, inflammation, and rupturing the bacterial cell wall. Mutations in this gene are associated with Ehlers-Danlos Syndrome. [provided by RefSeq, Dec 2018]

C1RL (HGNC:21265): (complement C1r subcomponent like) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in zymogen activation. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1R	NM_001733.7	c.426C>A	p.Asp142Glu	missense_variant, splice_region_variant	Exon 4 of 11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.468C>A	p.Asp156Glu	missense_variant, splice_region_variant	Exon 4 of 11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.426C>A	p.Asp142Glu	missense_variant, splice_region_variant	Exon 4 of 11		NM_001733.7	ENSP00000497341.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	.;.;T;T;T;.;T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;.;T;D;D;D;D;D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.7	.;.;D;D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	.;.;D;D;D;D;D;D
Sift4G	Uncertain	0.016	.;.;D;.;.;.;.;T
Polyphen		0.79, 0.99	.;.;P;D;.;.;.;.
Vest4		0.66, 0.65, 0.66
MutPred		0.76		Gain of disorder (P = 0.1513);Gain of disorder (P = 0.1513);.;.;.;.;.;.;
MVP		0.97
ClinPred		0.99	D
GERP RS		4.4
gMVP		0.66

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147288661; hg19: chr12-7242328;